SK287303B6 - Method for preparing an (S)-3-cyano-5-methylhexanoic acid, method and intermediates useful in the preparing of pregabalin - Google Patents

Abstract

This invention provides a method of making (S)-3-cyano-5- methylhexanoic acid of the formula (5), wherein X is CO2H or CO2-Y, and where Y is cation, method comprising asymmetric catalytic hydrogenation of an alkene of the formula (4) in the presence of a chiral catalyst. The invention also provides intermediates useful in the production of pregabalin. Method of making pregabalin comprising asymmetric catalytic hydrogenation of an alkene of the formula (4a), where Y is cation in the presence of a chiral catalyst,whereupon to perform reduction of the cyano group and protonation in formation free acid.

Description

The present invention relates to a process for the preparation of a (S) -3-cyano-5-methylhexanoic acid derivative, an intermediate for the preparation of pregabalin and a process for the preparation of pregabalin. Pregabalin is suitable for the treatment and prevention of seizure disorders, pain and psychotic disorders.

BACKGROUND OF THE INVENTION (S) - (+) - 3- (Aminomethyl) -5-methylhexanoic acid is commonly known as pregabalin. The compound is also called (S) - (+) - β-isobutyl-γ-aminobutyric acid, (S) -isobutyl-GABA and CI-1008.

Pregabalin is reported in relation to the endogenous inhibitory neurotransmitter γ-aminobutyric acid or GABA, which is involved in the regulation of neuronal activity of the brain. Pregabalin has an anti-seizure effect as described by Silverman et al., U.S. Patent 5,563,175.

Other indications of pregabalin are also currently being monitored (see, e.g., Gugleitta et al., U.S. Patent 6,127,418; and Singh et al., U.S. Patent 6,001,876).

A seizure is defined as excessive unsynchronized neuronal activity that disrupts normal brain function. It is believed that seizures can be controlled by regulating the concentration of the nerve mediator GABA. When the concentration of GABA in the brain drops below the cut-off level, seizures occur (Karlsson et al., Biochem. Pharmacol., 1974; 23: 3053). Once the brain GABA levels rise during convulsions, seizures end (Hayashi, Physiol. (London), 1959; 145: 570).

Due to the importance of GABA as a nerve mediator and its effect on convulsive conditions and other motor dysfunctions, various approaches to increasing the concentration of GABA in the brain have been tried.

In one method, compounds that activate L-glutamic acid decarboxylase (GAD) are used to increase GABA concentration, since GAD and GABA concentrations fluctuate concurrently, and increased GAD concentrations result in increased GABA concentrations (Janssens de Varebeke et al., Biochem. Pharmacol. , 1983; 32: 2751; Loscher, Biochem. Pharmacol., 1982; 31: 837; Phillips et al., Biochem. Pharmacol., 1982; 31: 2257).

E.g. The racemic compound (±) -3- (aminomethyl) -5-methylhexanoic acid (racemic isobutyl-GABA), which is a GAD activator, has the ability to suppress seizures by avoiding the undesirable side effect of ataxia.

The anticonvulsant effect of racemic isobutyl-GABA is primarily attributed to the S-enantiomer (pregabalin). That is, the S-enantiomer of isobutyl-GABA has a better anticonvulsant effect than the R-enantiomer (see, e.g., Yuen et al., Bioorganic & Medicinal Chemistry Letters, 1994; 4: 823).

Thus, the commercial advantage of pregabalin requires an efficient process for preparing the S-enantiomer substantially free of the R-enantiomer.

Various methods are used to prepare pregabalin. Typically, a racemic mixture is synthesized and then subsequently resolved into its R- and S-enantiomers (see U.S. Patent 5,563,175 for synthesis via an azide intermediate).

Another method uses potentially unstable nitro compounds, including nitromethane, and an intermediate that is reduced to an amine in a strongly exothermic and dangerous reaction. This synthesis also uses lithium bis (trimethylsilylamide) in a reaction that must be performed at -78 ° C (Andruszkiewicz et al., Synthesis, 1989: 953).

Recently, the racemate has been prepared by "malonate" synthesis and Hofmann synthesis (US Pat. Nos. 5,840,956; 5,637,767, 5,629,447 and 5,616,793). According to these methods, the classical racemate resolution method is used to obtain pregabalin.

Conventional resolution involves the preparation of a salt with a chiral resolving agent for resolution and purification of the desired S-enantiomer. This includes a characteristic manufacturing process and also considerable additional costs associated with the cleavage agent.

Partial recycling of the partitioning agent can be carried out, but it requires additional processing and costs, as well as the associated waste generation. Moreover, the undesired R-enantiomer cannot be efficiently recycled and is eventually discarded as waste. Thus, the maximum theoretical yield of pregabalin is 50%, since only half the racemate is the desired product.

This reduces the efficient production efficiency (the amount that can be produced at a given reactor capacity), which is part of the production cost and capacity.

Pregabalin was synthesized directly using several different synthetic schemes. One method involves the use of n-butyllithium at low temperature (<35 ° C) under carefully controlled conditions.

This synthetic route requires the use of (4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone as a chiral auxiliary to introduce the stereochemical configuration required for the final product (U.S. Patent 5,563,175).

While these general concepts provide the target compound with high enantiomeric purity, they are not practical for large-scale synthesis because they use expensive reagents that are difficult to process and also special cryogenic equipment to achieve the desired operating temperature.

Since pregabalin is obtained as a commercial pharmaceutical product, there is a need for an efficient, cost-effective and safe process for its large-scale synthesis. In order to be profitable for industrial production, this process must be highly enantioselective, for example, that the product is formed with a considerable excess of the correct enantiomer.

It is an object of the present invention to provide such a process by an asymmetric hydrogenation process.

Asymmetric hydrogenation procedures are known for some compounds. Burk et al., In WO 99/31041 and WO 99/52852 disclose the asymmetric hydrogenation of β-substituted and β, β-disubstituted itaconic acid derivatives to provide enantiomerically enriched 2-substituted succinic acid derivatives.

Itaconic substrates have two carboxyl groups which provide the necessary steric and electron configuration to control hydrogenation to produce the enriched enantiomer.

The disclosures disclose that salt forms of the formula RR'C = C (CO ₂ Me) CH ₂ CO ₂ 'Y ⁺ are required to obtain hydrogenated products having at least 95% enantiomeric excess.

According to U.S. Pat. No. 4,923,988, asymmetric hydrogenation does not work well on substrates having an isobutyl group.

We have now found that an isobutylcyanocarboxylic acid, salt or ester substrate of the formula iPrCH = C (CN) CH ₂ CO ₂ R can be selectively hydrogenated to provide an enantiomerically enriched nitrile derivative which can subsequently be hydrogenated to produce substantially pure pregabalin.

This selectivity is particularly surprisingly due to the dramatic differences in the steric configuration and the inducing effects of the nitrile residue compared to the carboxyl group.

In fact, there is no guidance in the art for successful asymmetric hydrogenation of any cyano-substituted carboxyolefin of this type.

SUMMARY OF THE INVENTION

The present invention is a process for the preparation of a (S) -3-cyano-5-methylhexanoic acid of formula (5) ^H 3 ^C \ ^^ / CN CH ₃ S (5), wherein X is CO ₂ H or CO ₂ Y and Y is a cation; in which an alkene of formula (4) is asymmetrically catalytic hydrogenated

in the presence of a chiral catalyst.

Preferred embodiments of the method include:

a process wherein X is CO ₂ -Y;

- a process wherein the chiral catalyst is a rhodium complex of (R, R) -DuPHOS ligand, wherein the ligand has the general formula (6)

wherein R is C 1 -C 6 alkyl such as methyl or ethyl;

a process wherein the chiral catalyst is [Rh (ligand) (COD)] BF ₄ ;

a process wherein the alkene is an E isomer or a Z isomer, or a mixture of these geometric isomers;

a process in which the cation is H ⁺ , an alkali metal or an alkaline earth metal such as potassium, or a salt of a primary amine or a salt of a secondary amine, wherein the amine is, for example, tert-butylaraine.

Said process for preparing a (S) -3-cyano-5-methylhexanoic acid derivative of formula (5) may further comprise first converting a carboxylic ester of formula (Ia)

] (Ia) wherein R ¹ is alkyl of 1 to 6 carbon atoms, such as ethyl, to the carboxylate salt of Formula (4a)

(4a), wherein Y is a cation.

The carboxylate salt may be isolated prior to hydrogenation or may be prepared in situ prior to hydrogenation. The obtained (S) -3-cyano-5-methylhexanoic acid carboxylate salt can be acidified to form (S) -3-cyano-5-methylhexanoic acid.

Said process for preparing the (S) -3-cyano-5-methylhexanoic acid derivative of general formula (5) may further comprise reducing the cyano group to form an amino group and, when Y is different from H ⁺ , by protonation by reaction with an acid to produce pregabalin.

The present invention also provides a compound of formula (4a)

(4a) wherein X is CO ₂ H or CO ₂ -Y and Y is a cation; as well as a compound of formula (Ia)

wherein R ¹ is alkyl of 1 to 6 carbon atoms such as ethyl.

The present invention also provides a process for the preparation of a compound of formula (7)

(7), wherein R ¹ is an alkyl of 1 to 6 carbon atoms in which an alkene of formula (Ia) is asymmetrically catalyticly hydrogenated

(1a) in the presence of a chiral catalyst.

The chiral catalyst is preferably a rhodium complex of (S, S) -DuPHOS ligand, wherein the ligand has the general formula (6)

(6) wherein R is alkyl of 1 to 6 carbon atoms, such as methyl or ethyl; or [Rh (ligand) (COD)] BF ₄ catalyst. The invention also provides a compound of formula (2) ^H 3 ^C \ x ^ \ _ ^ CN ^ COO'Y ^Cii 3 (2), wherein Y is a cation.

The present invention also provides a process for the preparation of pregabalin, wherein an alkene of formula (4a) is asymmetrically catalyticly hydrogenated.

wherein Y is a cation, in the presence of a chiral catalyst, and then cyano reduction and protonation are performed to give the free acid.

The invention provides an efficient process for preparing (S) -3- (aminomethyl) -5-methylhexanoic acid, pregabalin.

The method comprises asymmetric hydrogenation of a cyano-substituted olefin to produce the (S) -3- (aminomethyl) -5-methylhexanoic acid cyanoprecursor.

The method further comprises the reaction to convert the cyano intermediate to (S) -3- (aminomethyl) -5-methylhexanoic acid.

The asymmetric synthesis of (S) -3- (aminomethyl) -5-methylhexanoic acid described herein results in substantial enrichment with pregabalin as compared to the undesired (R) -3- (aminomethyl) -5-methylhexanoic acid. The R-enantiomer is produced as only a small percentage of the final product.

The present invention offers several advantages over the prior art processes of pregabalin production. For example, production of the undesired R-enantiomer and subsequent disposal of this waste is minimized.

Because the S-enantiomer is greatly enriched in the resulting product, the asymmetric procedure is more efficient.

In addition, this process does not require the use of hazardous nitro compounds, expensive chiral auxiliaries, or the low temperatures required in the prior art.

In addition, in contrast to conventional chiral excipient solutions or routes that require stoichiometric amounts of the chiral agent, this synthesis utilizes substoichiometric amounts of the chiral agent as a catalyst.

Thus, the process of the present invention has economic as well as environmental benefits.

Detailed description of the invention *

As used herein, the term "lower alkyl" or "alkyl" means a straight or branched hydrocarbon having 1 to 6 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl , tert-butyl, n-pentyl, n-hexyl and the like.

The term "aryl" means an aromatic carbocyclic group having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings wherein at least one is aromatic (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl) , anthryl or phenanthryl).

The aryl group may be unsubstituted or substituted by 1 to 3 substituents selected from alkyl, O-alkyl and S-alkyl, OH, SH, -CN, halogen, 1,3-dioxolanyl, CF ₃ , NO _2> NH ₂ , NHCH ₃ , N (CH ₃ ) ₂ , NHCO-alkyl, - (CH ₂ ) _m CO ₂ H, - (CH ₂ ) _m CO ₂ -alkyl, - (CH ₂ ) m SO ₃ H, -NH alkyl, -N (alkyl) ₂ , - (CH ₂ ) n, PO ₃ H ₂ , - (CH ₂ ) _m PO ₃ (alkyl) ₂ , - (CH ₂ ) _m SO ₂ NH ₂ and - (CH ₂ ) _m SO ₂ NH-alkyl, wherein alkyl is defined and m is 0, 1, 2 or 3.

A preferred aryl group according to the invention is phenyl. Typical substituted aryl groups include methylphenyl, 4-methoxybiphenyl, 3-chloraphth-1-yl and dimethylaminophenyl.

The term "arylalkyl" means an alkyl residue (as defined) substituted with an aryl residue (also defined). Examples include benzyl and 2-naphthylethyl.

A description of all articles and references in this application, including patents, is incorporated herein by reference.

The present invention provides an efficient synthesis of (S) -3- (aminomethyl) -5-methylhexanoic acid (pregabalin). This synthesis is shown in Scheme 1.

Scheme 1

wherein R ¹ is lower alkyl, aryl, arylalkyl or allyl; and Y is a cation, and preferably H ⁺ , a salt of a primary or secondary amine, an alkaline earth metal such as tert-butyl ammonium, or an alkali metal such as sodium.

As shown in Scheme 1, the metal salt 2 (where Y is, for example, potassium) of a cyanoalkanoic acid can be obtained from the cyanohexenoate ester 1a or 1b by sequential asymmetric hydrogenation and hydrolysis of the ester to the free acid or salt.

Subsequent reduction of the nitrile 2 by conventional hydrogenation with a catalyst such as nickel, followed by acidification of the carboxylate salt provides pregabalin.

These steps may optionally be reversed so that the substrate for asymmetric hydrogenation is an acid or salt of 4 h ₃ c.

wherein X is CO ₂ H or CO ₂ -Y, and Y is a cation. Compound 4 may exist as a single E or Z geometric isomer or as a mixture thereof.

Salts can be formed by reacting the free acid (X is CO ₂ H) with a strong base, such as a metal hydroxide, e.g. KOH. Alternatively, salts may be formed, for example, with a reversible WH +, such as that derived from amine (W) or fossil (W).

Preferred are C 1-10 alkylamines and cycloalkylamines, especially tert-butylamine. Tertiary amines such as triethylamine can also be used.

Subsequent reduction of the nitrile 2 by standard methods, again followed by acidification of the carboxylate salt, provides pregabalin.

In the general synthesis of pregabalin of Scheme 1, the cyanoolefin compound 1a or 1b undergoes ester hydrolysis and asymmetric hydrogenation to form the desired enantiomer of 3-cyano-5-methylhexanoic acid or the corresponding carboxylate salt 2. The olefin substrate may be a single E or Z geometric isomer or mixture.

Subsequent reduction of the nitrile 2, followed by acidification of the carboxylate salt, provides pregabalin.

The asymmetric hydrogenation step is carried out in the presence of a chiral catalyst, preferably a rhodium complex of (R, R) -DuPHOS or (S, S) -DuPHOS ligand, commercially available from Strem Chemicals, Inc. (7 Mulliken Way, Newburyport, MA 01950-4098) and Chirotech Technology Limited (Cambridge Science Park, Cambridge, Great Britain) (see US Patent 5,532,395 and 5,171,892).

The ligand preferably has the formula

chiral DuPHOS chiral DuPHOS wherein R is lower alkyl.

Preferred alkyl groups for R are n-alkyl groups such as methyl, ethyl, propyl, butyl, pentyl or hexyl. Preferred alkyl groups for R are methyl or ethyl.

Other catalysts that may be used include rhodium complexes of chiral BPE and chiral DIPAMP having the formulas:

chiral BPE

These catalysts are generally complexed with 1,5-cyclooctadiene (COD). These agents are fully described by Burk et al. in J. Am. Chem. Soc., 1995; 117: 9375.

The asymmetric hydrogenation reaction is carried out under a hydrogen atmosphere and preferably in a protic solvent such as methanol, ethanol, isopropanol or a mixture of these alcohols with water.

Cyanohexanoate starting materials are readily available (Yamamoto et al., Bull. Chem. Soc. Jap., 1985; 58: 3397). They may be prepared according to Scheme 2 above.

Scheme 2

h ₃ c —CHO + .CN í] H, C Dabco ^J j \ cN h ₃ c clay ₂ >. _z h ₃ c 0 ch ₂ OŔ ² EtO ₂ CCI 1 cat. Pd (OAc) ₂ H ₃ C _X or h ₃ c _x γΥ ' PPh ₃ , R ¹ OH ΪΎ CH ₃ COCl; base I n CHn CH ₇ CO (280 psi) ^CH 3 = CO ₂ R ^J la

wherein R ¹ is as defined in Scheme 1 and R ² is COCH ₃ or CO ₂ alkyl.

In the synthesis of compound Ia according to Scheme 2, the amine catalyzed addition of acrylonitrile (i.e., the Baylis-Hillman reaction) to the 2-methylpropanal affords the cyanoallyl alcohol.

Typical amines used to catalyze condensation include reagents such as 1,4-diazabicyclo [2.2.2] octane (Dabco).

The cyanoallyl alcohol is then converted either to an alkyl carbonate (e.g. by reaction with an alkyl haloformate such as ethyl chloroformate) or to the corresponding acetate (by reaction with acetic anhydride or acetyl chloride). The resulting 2- (2-methylpropyl) prop-2-enenitrile is then subjected to palladium catalyzed carbonylation to form ethyl 3-cyano-5-methylhex-3-enoate 1a (e.g. wherein R ¹ is methyl or ethyl).

In one embodiment of the invention shown in Scheme 3, asymmetric hydrogenation to 1a (wherein R ¹ is, for example, ethyl) is first performed to form (S) -3-cyano-5-ethylhexanoic acid ester 3.

The use of a bisphospholane series chiral (S, S) hydrogenation catalyst, e.g. [(S, S) -Me-DuPHOS] R h (COD) ⁺ BF ₄ 'on ester substrates (e.g., R ¹ is alkyl) provides the products enriched in the desired S-enantiomer.

The ester 3 is then hydrolyzed to the acid or salt 2. Scheme 3 below shows this synthetic process where Y is defined for Scheme 1.

By substituting the [(R, R) -Me-DuPHOS] Rh (COD) ⁺ BF ₄ 'catalyst, the hydrogenation product is enriched in (R) -3-cyano-5-methylhexanoic acid ethyl ester. These hydrogenation procedures typically allow for at least 90% conversion of the substrate and enantiomeric enrichment of 20-25% (subject to error).

Further enrichment of the product can be accomplished by selective recrystallization with a chiral resolving agent as described.

Scheme 3 h ₃ c

asymmetric hydrogenation 1a

hydrolysis

A preferred embodiment of the invention is shown in Scheme 4 wherein the ester 1a is first hydrolyzed to the 3-hexanoic acid salt 4 (e.g., 4a as shown in Scheme 4 wherein Y is sodium or potassium).

The cyanohexanoic acid salt 4a is then hydrogenated to the salt 2. The cyanohexanoic acid salt may be isolated or may be prepared in situ prior to hydrogenation.

Scheme 4 illustrates this preferred embodiment wherein Y is defined for Scheme 1.

A particular feature of the hydrogenation of the salt 4a is that the desired S-enantiomer is obtained using a chiral (R, R) bisphospholane catalyst, e.g. [(R, R) -MeDuPHOS] Rh (COD) ⁺ BF ₄ '.

This represents an unexpected change in the absolute configuration compared to the hydrogenation of the ester substrate 1a (Scheme 3).

In addition, the enantioselectivity achieved in the hydrogenation of salt 4a is much higher, typically at least about 95% (subject to errors).

The choice of cation Y does not appear to be critical since comparable enantioselectivities are observed with metal cations (e.g. K ⁺ ) and non-metal cations (e.g. tert-butylammonium).

Without being limited by theory, the different properties of substrates 1a and 4a may result from bonding interactions between the functional groups of each substrate and the rhodium nucleus in the catalyst, which may act alternately in both direction and surface selectivity during olefin hydrogenation. Thus, in the hydrogenation of ester 1a, the cyano substituent may be involved in the coupling to the catalyst. This effect appears to be almost suppressed in the hydrogenation of salt 4a, in which the carboxyl group bond is likely to be dominant.

Scheme 4

asymmetric hydrogenation -------->

As a further embodiment, the invention provides novel compounds of formula (4)

(4), wherein X is CO ₂ H or CO ₂ -Y, and wherein Y is the cation described in Scheme 1. These compounds are useful substrates in the synthesis of pregabalin.

In another preferred embodiment of the invention, the final product pregabalin can be selectively recrystallized with (S) -mandelic acid to obtain an even higher enrichment of the desired S-enantiomer.

Thus, high levels of the (R) -enantiomer (up to at least 50%) can be removed by classical resolution with the (S) -mandelic acid salt (U.S. Patent No. 5,840,956, U.S. Patent No. 5,637,767).

Suitable solvents for these selective recrystallizations include, for example, water or an alcohol (e.g., methanol, ethanol and isopropanol, and the like) or a mixture of water and an alcohol.

Usually an excess of mandelic acid is used. It is also known that mandelic acid can be used in combination with another acid.

Alternatively, pregabalin containing a low level (<1%) of the (R) -enantiomer may be enriched to> 99.9% of the (S) -enantiomer by simple recrystallization e.g. from water / isopropyl alcohol.

Pregabalin containing a higher level (up to 3.5%) of the (R) -enantiomer may also be enriched by simple recrystallization, for example from water / isopropyl alcohol, although gradual recrystallizations are usually required to achieve> 99.9% of the (S) -enantiomer.

As used herein, "substantially pure" pregabalin means at least about 95% by weight of the S-enantiomer and not more than about 5% of the R-enantiomer.

The following detailed examples further illustrate individual embodiments of the invention. These examples are not intended to limit the scope of the invention and are not to be construed as limiting.

The starting compounds and various intermediates can be obtained from commercial sources, prepared from commercially available compounds, or prepared using known synthetic methods known to those skilled in the art of organic chemistry.

Preparation of the starting compounds

-Hydroxy-4-methyl-2-methylene-pentanenitrile

A 250 ml three-necked round bottom flask with overhead stirring was charged with 0.36 g (1.6 mmol) of 2,6-di-tert-butyl-4-methylphenol, 37 g (0.33 mol) of 1,4-diazabicyclo- [2.2.2] octane, 60 ml (0.66 mol) isobutyraldehyde, 52 ml (0.79 mol) acrylonitrile and 7.2 ml (0.4 mol) water.

The reaction mixture was stirred at 50 ° C for 24 hours, cooled to 25 ° C and poured into a solution of 33 ml (0.38 mol) of hydrochloric acid and 100 ml of water. The product is extracted with 120 ml of methylene chloride.

The combined methylene chloride layers were concentrated by rotary evaporation to give 79.9 g (96.7%) of 3-hydroxy-4-methyl-2-methylene-pentanenitrile as a yellow oil (which may solidify on standing to a white solid), 96.7 % (area under the curve) by HPLC analysis, which can be used in the next step without further purification.

Carbonic acid 2-cyano-1-isopropyl-allyl-ethyl ester

1 N nitrogen purged three-necked round bottom flask with overhead stirring is charged with 150 g (1.2 mol) of 3-hydroxy-4-methyl-2-methylene-pentanenitrile, 1.0 L of methylene chloride and 170 ml (2.1 mol) of pyridine . The solution is cooled to 10-15 ° C in an ice bath.

A mixture of 0.5 L of methylene chloride and 200 mL (2.1 mol) of ethyl chloroformate is slowly added via a 1 L split funnel while maintaining the reaction temperature at 20 ° C ± 5 ° C. The reaction mixture was stirred at 22 ° C ± 3 ° C for about two hours.

The reaction solution was poured into a 6 L separatory funnel containing 200 mL (2.3 mol) of hydrochloric acid and 1.25 L of water. The lower organic layer was washed again with a solution of 60 mL (0.7 mol) HCl and 0.5 L water.

Dry the organic layer over anhydrous magnesium sulfate (30 g), filter and concentrate by rotary evaporation to give 226 g of 2-cyano-1-isopropyl-allyl-ethyl ester of carbonic acid as a yellow oil, which can be used in the next step without further purification. .

Acetic acid 2-cyano-1-isopropyl-allyl ester (using acetyl chloride)

A nitrogen-purged three-necked round bottom flask with overhead stirring was charged with 50 g (0.4 mol) of 3-hydroxy-4-methyl-2-methylene-pentanenitrile, 0.4 L of methylene chloride and 80 ml (1 mol) of pyridine.

The solution is cooled to 10-15 ° C in an ice bath. A mixture of 100 ml of methylene chloride and 43 ml (0.6 mol) of acetyl chloride is slowly added via a 500 ml split-funnel while maintaining the reaction temperature at 25 ° C ± 5 ° C. The reaction mixture was stirred at 22 ° C ± 3 ° C for about an additional hour.

The reaction solution was poured into a 4 L separatory funnel containing 85 mL (1.0 mol) of hydrochloric acid and 750 mL of water. The lower organic layer was washed again with a solution of 20 mL (0.2 mol) HCl and 250 mL water.

The organic layer was dried over anhydrous magnesium sulfate (20 g), filtered and concentrated by rotary evaporation to give 66 g of acetic acid 2-cyano-1-isopropyl-allyl ester as a yellow oil, which can be used in the next step without further purification.

Acetic acid 2-cyano-1-isopropyl-allyl ester (using acetic anhydride)

Acethanhydride (40 mL, 0.45 mol) was charged to a 500 mL four-necked round-bottomed flask equipped with an overhead stirrer, temperature probe, reflux condenser and nitrogen inlet. This solution was heated to 50 ° C and after 35 minutes a solution of 3-hydroxy-4-methyl-2-methylene-pentanenitrile (50 g, 0.40 mol) and 4- (dimethylamino) pyridine (1.5 g) was added. in tetrahydrofuran (25 mL). A temperature of 50 to 63 ° C is maintained without external heating.

After the addition was complete, the reaction mixture was heated at 60 ° C for 75 minutes. The solution was cooled to 30 ° C and the cooled reaction mixture was diluted with 30 mL of tert-butyl methyl ether (MTBE) and 25 mL of water.

The mixture was cooled to 10 ° C and a solution of 50% aqueous sodium hydroxide (37 g, 0.46 mol) diluted with 45 mL of water was added while cooling to maintain the temperature at about 15 ° C.

9.8 g (0.12 mol) of 50% aqueous sodium hydroxide are added dropwise to adjust the final pH to a final pH of 9.4. After addition of 10 ml of water and 10 to 15 ml of MTBE, the reaction mixture is phased and separated.

The upper organic layer of the product was separated and washed with 25 mL of brine, dried over magnesium sulfate and concentrated in vacuo to afford 63.7 g (95%) of acetic acid 2-cyano-1-isopropyl-allyl ester as a pale yellow oil.

Ethyl 3-cyano-5-methyl-hex-3-enoate, Et

The high pressure high stirred reactor was charged with 3.0 g (13.4 mmol) of palladium acetate, 7.0 g (26.8 mmol) of triphenylphosphine and 226 g (0.92 mol) of crude oil containing 2-cyano-1-isopropyl- allyl ethyl ester of carbonic acid and 500 ml of ethanol.

Carbon monoxide is introduced at 280-300 psi and the mixture is heated to 50 ° C overnight with stirring. The red-brown solution was filtered through celite to remove solids.

The filtrate was concentrated by rotary evaporation to give 165 g of a crude yellow oil product, ethyl 3-cyano-5-methylhex-3-enoate having a content of 84% (area) as determined by gas chromatography (GC) as a mixture of E and Z isomers.

The crude product can be used without further purification or optionally purified by vacuum distillation (80-133 Pa at 60-70 ° C) to give a colorless oil having a content> 95% (area) as determined by GC.

Ethyl 3-cyano-5-methylhex-3-enoate (using KBr)

The high pressure high stirred reactor was charged with palladium acetate (0.52 g, 2.3 mmol), triphenylphosphine (0.65 g, 2.3 mmol), potassium bromide (5.5 g, 4.8 mmol) and petroleum containing Carbonic acid 2-cyano-1-isopropyl-allyl-ethyl ester (240 g, 1.2 mol), triethylamine (2.2 g, 22 mmol), ethanol 2B (45 mL) and acetonitrile (200 mL).

Carbon monoxide is introduced at 50 psi and the mixture is heated to 50 ° C overnight with stirring. The reactor pressure is released to 10 to 103 kPa after about 1, 3 and 6 hours and refilled with carbon monoxide to 343 kPa.

The reaction mixture was filtered through celite to remove solids. The filtrate was concentrated in vacuo and hexane (800 mL) was added.

The resulting mixture was washed twice with 500 ml of water and the hexane was removed in vacuo to give 147 g of crude ethyl 3-cyano-5-methylhex-3-enoate as an oil.

This crude product was purified by fractional distillation (93.3 Pa at 60-70 ° C).

Ethyl 3-cyano-5-methylhex-3-enoate (using NaBr)

The high pressure high stirred reactor was charged with 0.5 g (0.5 mmol) of palladium (0) tris (dibenzylideneacetone), 0.5 g (2.0 mmol) of triphenylphosphine, 0.5 g (5.0 mmol) of sodium bromide , 4.5 mL (25.0 mmol) of diisopropylethylamine, 8.35 g (50.0 mmol) of acetic acid 2-cyano-1-isopropyl-allyl ester and 100 mL of ethanol.

Carbon monoxide is introduced at 40-50 psi, and the mixture is heated at 50 ° C for 24 hours with stirring. Filter the brown solution through celite to remove solids.

The filtrate was concentrated by rotary evaporation. The concentrated reaction mixture was diluted with 150 mL of methyl tert-butyl ether and washed with water.

The solvent was removed on a rotary evaporator to give 7.7 g of a crude yellow oil of ethyl 3-cyano-5-methyl-hex-3-enoate (85% content by GC analysis). The crude product can be used without further purification or possibly purified by vacuum distillation (80-133 Pa at 60-70 ° C).

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Synthesis of 3-cyano-5-methylhex-3-enoic acid salts

A. 3-Cyano-5-methylhex-3-enoic acid tert-butylammonium salt

1) LiOH H ₂ O THF

2) HCl

3) Bi / N 2 / EtOAc

substance MH number mmol Ethyl 3-cyano-5-methyl-hex-3-enoate 181.24 20.02 g 110 LiOH H ₂ O 41,96 13,0 g 310 Tetrahydrofuran 75 ml Water 25 ml Hydrochloric acid (2N) how much is needed Ethyl acetate how much is needed t-Butylamine 73.14 9,27 g 127

Ethyl 3-cyano-5-methylhex-3-enoate (mixture of E and Z isomers) and lithium hydroxide hydrate were suspended in a mixture of tetrahydrofuran and water. The suspension was stirred vigorously at room temperature for 4 hours. The mixture was acidified to pH 2 (3N HCl) and extracted into ethyl acetate (3 x 150 mL).

The combined organic layers were dried (MgSO ₄ ) and the solvent removed in vacuo to give crude 3-cyano-5-methylhex-3-enoic acid. The crude acid was dissolved in ethyl acetate (400 mL) and a solution of tert-butylamine in ethyl acetate (20 mL) was added. The temperature of the solution rises by approximately 10 ° C as a mass of a white crystalline solid precipitate.

The product was collected by filtration and dried in vacuo. Yield 22.15 g, 97.0 mmol, 89%.

Al. tert-Butylammonium 3-cyano-5-methylhex-3-enoate (alternative method)

To an appropriately sized three-necked round-bottomed flask was charged 50 g of an oil containing ethyl 3-cyano-5-methylhex-3-enoate (29.9 g contained, 165 mmol).

A solution of KOH (91%, 10.2 g, 165.1 mmol) in 50 mL of water was poured into the ester solution over 20 minutes and the solution was allowed to stir for an additional hour. Water (50 mL) was added and the solution was concentrated to 80 mL in vacuo.

The aqueous solution was washed with MTBE (100 mL). The solution containing the MTBE product is concentrated in vacuo.

The resulting oil was dissolved in isopropyl alcohol (58 mL) and heptane (85 mL) and this solution was filtered through celite. The filter cake was washed with a mixture of isopropyl alcohol (58 mL) and heptane (85 mL).

tert-Butylamine is added to the solution to form a dense gel suspension. The suspension is heated at reflux to obtain a solution. The solution was allowed to slowly cool to room temperature.

The resulting suspension was cooled to 0-5 ° C for 1.5 hours, then filtered and washed with a mixture of isopropyl alcohol (50 mL) and heptane (150 mL).

The solid is dried under vacuum at 45-50 ° C to give 23.1 g (62%) of tert-butylammonium 3-cyano-5-methyl-hex-3-enoate as a white solid which is a mixture of E and From isomers.

The Z isomers can be obtained in more than 95% isomeric purity by recrystallization from isopropyl alcohol and heptane.

B. Potassium salt of 3-cyano-5-methylhex-3-enoic acid

KOH / MeOH -; -----> -

substance source MH number mmol Ethyl 3-cyano-5-methylhex-3-enoate PD 61966X130 181.24 90,8 g 501 Potassium hydroxide 85% Aldrich 56.11 33.1 g 501 methanol Fisher 90 ml tert-Butyl methyl ether Fisher 900 ml

Potassium hydroxide was dissolved in methanol (70 mL) and added to rapidly stirred ethyl 3-cyano-5-methylhex-3-enoate (mixture of E and Z geometric isomers) at such a rate that the temperature was kept below 45 ° C. .

Rinse the remaining methanolic potassium hydroxide into the mixture with additional methanol (2 x 10 mL). The mixture was heated at 45 ° C for 1 hour and then allowed to cool to room temperature during which time a crystalline solid formed. Tert-Butyl methyl ether (600 mL) was added slowly with vigorous stirring.

The solid was collected on a filter frit bed, washed with tert-butyl methyl ether (3 x 100 mL), and dried to give the title compound. Yield 83.9 g, 43.9 mmol, 88%.

Example 2

Asymmetric hydrogenation of 3-cyano-5-methylhex-3-enoic acid salts

A. (S) -3-Cyano-5-methylhexanoic acid tert-butylammonium salt

[(JJ?) - MeDuPHOS] Rh (COD) ' ^t ' BF ₄ ·

----------------------- _> ^H 2

MeOH

^ CO ₂ ' ⁺ H ₃ NBu ^t

substance MH number mmol 3-Cyano-5-methylhex-3-enoic acid tert-butylammonium salt 226.33 19,0 g 84 [(R, R) -MeDuPHOS] Rh (COD) BF f 604 4 9.6 mg 0,082 methanol 32 200 ml hydrogen 2 44 psi (3 bar)

The round-bottom flask was charged with 3-cyano-5-methylhex-3-enoic acid tert-butylammonium salt (from Example 1) and [(R, R) -MeDuPHOS] Rh (COD) BFf under a nitrogen atmosphere.

Deoxygenated methanol is added via syringe and the solution is deoxygenated by repeated partial suction and refilled with nitrogen.

The 600 mL PARK pressure vessel was purged three times with hydrogen by pressurizing and releasing the pressure. The vessel was then heated to 55 ° C.

The substrate and catalyst solution is transferred to the reactor via a cannula and the vessel is purged again with hydrogen before final pressurization to 0.3 MPa. Stirring begins and hydrogen uptake begins.

The vessel was repeatedly pressurized to 0.3 MPa until hydrogen uptake ceased (about 45 minutes). After stirring under pressure at 55 ° C for an additional hour, heating is discontinued. Once the reactor was warmed to room temperature, the hydrogen pressure was released, the vessel was purged with nitrogen, and the reaction mixture was transferred to a round bottom flask. The solvent was removed in vacuo to give the crude product.

A small sample is taken and converted to (S) -3-cyano-5-methylhexanoic acid by treatment with aqueous hydrochloric acid and extraction into dichloromethane.

GC analysis shows 100% conversion to reduced cyanoalkane with 95% (S) (subject to errors).

B. Potassium salt of (S) -3-cyano-5-methylhexanoic acid (substrate for catalyst (S / C) ratio 1000/1)

[(.RJ?) -MeDuPHOS] Rh (COD) ⁺ BF ₄

MeOH

substance MH number mmol Potassium salt of 3-cyano-5-methylhex-3-enoic acid 191.3 11.03 g 57.7 [(R, R) -MeDuPHOS] Rh (COD) BF ₄ ' 604 11 mg in 10 mL MeOH 18.2 x 10 ^-3 S / C = 1000 ^{nm, n} 7wt. methanol 32 100 ml hydrogen 2 0.4 MPa

The glass cylinder was charged with 3-cyano-5-methylhex-3-enoic acid potassium salt (from Example IB) and methanol and placed in a 600 mL PARR hydrogenation vessel.

The vessel was purged with nitrogen and then hydrogen by pressurizing to 60 psi and stirring for 10 minutes to ensure complete equilibration of the gases and releasing the pressure over five cycles. The vessel was warmed to 45 ° C and a solution of [(R, R) -MeDuPHOS] Rh (COD) BF ₄ 'in deoxygenated methanol (11 mg in 10 mL) was added via syringe. The vessel was purged again with hydrogen and then pressurized to 60 psi with stirring.

Hydrogen is added regularly to maintain a pressure of between 50 and 65 psi. Hydrogen uptake is stopped after 120 minutes. After 2 hours, the mixture is cooled to room temperature, the pressure is released and the solvent is removed to give the crude product.

A small sample is taken and acidified with 1N HCl to give (S) -3-cyano-5-methylhexanoic acid. GC analysis shows> 99% conversion with 96.7% S isomer (subject to errors).

C. (S) -3-Cyano-5-methylhexanoic acid potassium salt (catalyst substrate (S / C) ratio 3 200 / 1,640 mmol)

[(2U?) - MeDuPHOS] Rh (COD) ⁺ BF ₄ *

MeOH

substance MH number mmol Potassium 3-cyano-5-methyl-hex-3-enoate 181.2 123 g 640 [(R, R) -MeDuPHOS] Rh (COD) BF ₄ ' 604 123 mg 0,204 methanol 32 1015 ml hydrogen 2 0.4 MPa

The glass cylinder was charged with potassium 3-cyano-5-methyl-hex-3-enoate (from Example IB) and methanol (1000 mL). The cylinder was placed in a 21 PARR hydrogenation vessel.

The vessel was purged with nitrogen and then hydrogen by pressurizing to 0.4 MPa and releasing the pressure over five cycles. The vessel was heated to 45 ° C.

A solution of [(R, R) -MeDuPHOS] Rh (COD) ⁺ BF ₄ 'in deoxygenated methanol (15 mL) was added via syringe. The vessel was again purged three times with hydrogen, then pressurized to 65 psi and stirring was started. Hydrogen was added regularly to maintain a pressure between 0.34 to 0.4 MPa.

Hydrogen uptake ceased after 2.5 hours, the vessel was cooled to room temperature and allowed to stir overnight. The pressure was released, the mixture was transferred to a flask, and the solvent was removed in vacuo to give the product.

A small sample was taken and converted to methyl (S) -cyano-5-methylhex-3-enoate. Analysis by gas chromatography showed> 99% conversion of 97.5% (except for errors).

D. (S) -3-Cyano-5-methylhexanoic acid tert-butylammonium salt (S / C ratio 2700 / 1.557 mmol)

- +

H ₃ NBu

H, MeOH [(AÄ) -MeDuPHOS] Rh (COD) ⁺ BF ₄ *

substance MH number mmol tert-Butylammonium-3-cyano-5-methyl-hex-3 -enoate 226.33 125.8 g 557 [(R, R) -MeDuPHOS] Rh (COD) ⁺ BF ₄ ' 604 12 5 mg 0, 082 methanol 32 200 ml hydrogen 2 0.34 - 0.4 MPa

The glass cylinder was charged with tert-butylammonium 3-cyano-5-methylhex-3-enoate and methanol (1000 mL). The cylinder was placed in a 21 PARR hydrogenation vessel.

The vessel was purged with nitrogen and then hydrogen by pressurizing to 0.4 MPa and releasing the pressure over five cycles. The vessel was then heated to 45 ° C. A solution of [(R, R) -MeDuPHOS] Rh (COD) ⁺ BF ₄ 'in deoxygenated methanol (15 mL) was added via syringe. The vessel was again purged three times with hydrogen, then pressurized to 0.45 MPa and stirring was started.

Hydrogen was added regularly to maintain the pressure between 0.34 - 0.45 MPa. Hydrogen uptake ceased after 4 hours, then after a further 1 hour the vessel was cooled to room temperature and allowed to stir overnight. The pressure was released, the mixture was transferred to a flask, and the solvent was removed in vacuo to give the product.

A small sample was taken and converted to methyl (S) -cyano-5-methylhex-3-enoate by reaction with methanol and 1N HCl. GC analysis showed> 99% conversion of 97.7% (with the exception of errors).

E. Potassium salt of 3-cyano-5-methylhexanoic acid formed in situ from ethyl 3-cyano-5-methylhex-3-enoate

1) K0H / H ₂ O / Me0H —-------------——_———> 2) [(JJ?) - McDuPHOS] Rh (COD) ⁺ BF ₄

H-, MeOH

substance MH number mmol Ethyl 3-cyano-5-methyl-hex-3-enoate 181.2 10.81 g 59.7 Potassium hydroxide 11,68 ml 58.4 [(R, R) -MeDuPHOS] RH (COD) BF ₄ 604 18.0 mg 29.8 x 10 ' ³ methanol 32 120 ml Water 18 18 ml hydrogen 2

The glass cylinder was charged with ethyl 3-cyano-5-methyl-hex-3-enoate (starting material), methanol (100 mL) and water (18 mL). Potassium hydroxide is added with stirring. The cylinder is placed in a 600 ml PARR hydrogenation vessel. The vessel was purged with nitrogen and then hydrogen by pressurizing to 60 psi and releasing the pressure for 5 cycles. The vessel was then heated to 55 ° C.

A solution of [(R, R) -MeDuPHOS] Rh (COD) ⁺ BF ₄ 'in deoxygenated methanol (18.0 mg in 20 mL) was added via syringe. The vessel was purged again with hydrogen, then pressurized to 60 psi with stirring. Hydrogen is added regularly to maintain the pressure between 0.34-0.40 MPa.

Hydrogen uptake ends after 5 hours. After an additional 1 hour, the mixture was cooled to room temperature and the pressure was released. The mixture was transferred to a flask and the solvent was removed in vacuo to give the product.

A small sample is taken and converted to (S) -cyano-5-methylhexanoic acid by treatment with 1N hydrochloric acid. GC analysis showed> 98.7% conversion to the desired cyanoalkane salt with 96.6% of the S isomer (except for errors).

Example 3

Hydrogenation of ethyl 3-cyano-5-methylhex-3-enoate

[(R, R) -MeDuPHOS] Rh (COD) ⁺ BF ₄ '

^H 2

MeOH

substance MH number mmol Ethyl 3-cyano-5-methylhex-3-enoate 181 0.36 g 2.00 [(R, R) -Me-DuPHOS] Rh (COD) BF ₄ - 604 1.2 mg 2 x 10 ' ³ methanol 5 ml hydrogen 0.4 MPa

A. The reaction is carried out in a 50 ml microreactor equipped with an injection tray and a valve. The microreactor is used in conjunction with a glass cylinder. Methanol is deoxygenated by four partial suction cycles and refilled with nitrogen while stirring.

A cylinder filled with ethyl 3-cyano-5-methyl-hex-3-enoate and a magnetic stir bar is placed in the microreactor and the microreactor is gradually assembled. The hydrogen atmosphere is introduced through three cycles of pressurizing the vessel with hydrogen and releasing the pressure. Methanol (4 ml) was added and the vessel was then placed in an oil bath on a stirring plate at 60 ° C and allowed to reach equilibrium temperature (internal temperature about 45 ° C). A small Schlenk tube is charged with [(R, R) -MeDuPHOS] Rh (COD) ⁺ BF ₄ 'and a nitrogen atmosphere is introduced through four partial suction cycles and again with nitrogen charging. The catalyst was dissolved in methanol to give a solution containing 1.2 mg of catalyst in 1 ml of solvent.

One milliliter of catalyst solution is added to the microreactor by syringe.

The vessel was again purged with 60 psi of hydrogen and depressurized for another four cycles. The vessel was then pressurized to 0.4 MPa with stirring until hydrogen absorption was judged to be complete (about 3 hours). The reactor is removed from the oil bath and allowed to cool. The pressure was then released and the solvent was removed in vacuo. GC analysis showed 99% conversion, 22.7% (R) (except for errors).

B. Following the general procedure of Example 3.1, 200 mg (1.190 mmol) of methyl 3-cyano-5-methylhex-3-enoate was dissolved in 3 mL of methanol and reacted with hydrogen gas (60 psi) in the presence of 43 mg (0). 06 mmol) [(R, R) -Me-DuPHOS] Rh (COD) ⁺ BF ₄ 'to provide 10% conversion to methyl 3-cyano-5-methylhexanoate having 33% (R) (s) except for errors).

Example 4

Synthesis of pregabalin

A. Conversion of (S) -3-cyano-5-methylhexanoic acid potassium salt to pregabalin

S-cyano acid, potassium salt (prepared as described in Example 2B, 94.9% of the S isomer, 8.0 g, 41.4 mmol) was charged together with potassium hydroxide (91%, flake, 44.0 mg total) weight, 40.0 mg net weight, 0.7 mmol), water (15 mL) and 2B EtOH (ie denatured with toluene) (10 mL) to a PARR flask containing sponge nickel catalyst (A-7000, Activated Metals and Chemicals, Inc., POBox 4130, Severville, TN 37864, 5 g, soaked with water).

The suspension is shaken on a PARR shaker under hydrogen at 50 psi at room temperature overnight.

The suspension is filtered through a Supercel plate. Rinse the filter cake with water (20 mL) and 2B EtOH (7 mL).

The combined filtrate was treated with glacial acetic acid (2.4 mL, 2.5 g, 41.6 mmol) and heated at 70 ° C for 30 min. The mixture was cooled to 0 ° C and the solid was collected by filtration, washed with isopropanol (50 mL) and dried to give 3.2 g of the product (20 mmol, 49% yield).

HPLC analysis of the substance showed 99.7% (area under the curve) of 3-isobutyl GABA. Enantiomeric analysis (HPLC) shows 3-isobutyl GABA as a mixture of isomers: 97.82% is the desired S-isomer (pregabalin) and 2.18% is the undesired R-isomer.

B. Conversion of (S) -3-cyano-5-methylhexanoic acid tert-butylammonium salt to pregabalin S-cyano acid tert-butylammonium salt (prepared or described in Example 2A, 97% S-isomer, 8.0 g, 35%) 0 mmol) was charged together with potassium hydroxide (91%, flake, 2.2 g total weight, 2.0 g net weight, 35.6 mmol), water (15 mL) and 2B EtOH (11 mL) to PARR flasks containing sponge-like nickel catalyst (A-7000, 5 g, soaked in water).

The suspension is shaken on a PARR shaker under hydrogen at 50 psi at room temperature overnight.

The suspension is filtered through a Supercel plate. Rinse the filter cake with water (20 mL) and 2B EtOH (ethanol denatured with toluene) (7 mL).

The combined filtrate was saturated with glacial acetic acid (4.1 mL, 4.3 g, 71.6 mmol). The resulting solution was heated to 70 ° C and then allowed to cool to room temperature.

The reaction slurry was then stirred at 0-5 ° C for 6 hours and filtered. The solid was rinsed with IPA (50 mL) and dried in a vacuum oven for 2 days to give a solid that weighed 3.4 g (61.0% overall yield).

HPLC analysis determined the product as 97.20% (area) of 3-isobutyl GABA, of which 99.92% was the desired S-isomer (pregabalin).

An argon-purified 600 mL pressure reactor was charged with tert-butylammonium 3-cyano-5-methyl-hex-3-enoate (prepared as described in Example 1A, 36 g, 159.1 mmol) and [(R, R) -Me -DuPHOS] Rh (COD) BF ₄ (0.054 g, 0.0894 mmol). The reactor was pressurized with argon (3 x 0.34 MPa).

360 ml of methanol are metered into a 1000 ml reactor. Methanol was pressure purged with argon (3 x 0.34 MPa). The methanol is then charged to a reactor containing the substrate and the catalyst. The solution was pressure purged with argon (3 x 50 psi) and then pressurized to 50 psi with hydrogen and stirred overnight at 27-33 ° C.

The hydrogen pressure is released and the solution is purged with argon. The solution was transferred to a flask containing a solution of potassium hydroxide (91%, 10.3 g, 167 mmol) in 90 mL of water.

Concentrate the solution to about 180 mL in vacuo. The concentrated solution was transferred to a 600 mL pressure reactor containing sponge A-7000 (12.0 g, 50% aqueous humidity). The solution was purged with argon (3 x 3 bar) and then the reactor was pressurized with hydrogen and stirred overnight.

The hydrogen pressure is released. The solution was purged with argon and filtered. The filter cake is washed with 90 ml of methanol. The filtrate was concentrated in vacuo to remove methanol and made up with 72 mL of isopropyl alcohol.

The solution is heated to 65 ° C. Add glacial acetic acid (9.4 mL, 171 mmol) and heat the solution to 73 ° C. The solution was quenched to 50 ° C, then cooled slowly to room temperature. The suspension is cooled to 0-5 ° C for 3.5 hours.

The suspension is filtered and the cake is washed with isopropyl alcohol.

The solid was dried under vacuum at 45 ° C to give 18.4 g (73%) of pregabalin as a white solid (99.89% S).

An argon-purified 170 L reactor was charged with tert-butylammonium 3-cyano-5-methyl-hex-3-enoate (10 kg, 44.2 mol, prepared as described in Example 1A) and [(R, R) - MeDuPHOS] Rh (COD) BF ₄ (0.015 kg, 0.0025 mol). The reactor was pressurized with argon (3 x 0.34 MPa).

A 170 L still is charged with 100 L of methanol.

The reactor is suctioned off under vacuum and then the vacuum is interrupted with argon. The distillation apparatus was pressurized to 0.34 MPa with argon and then vented. The entire purification procedure is repeated twice.

Methanol is charged to the reactor containing the substrate and the catalyst. The solution was pressure purged with argon (3 x 50 psi) and then pressurized to 50 psi with hydrogen and stirred overnight at 27-33 ° C.

The hydrogen pressure is released and the solution is purged with nitrogen. The solution was filtered into a 170 L distillation apparatus containing a solution of potassium hydroxide (91%, 2.9 kg, 46.4 mol) in 25 L water. A 5 liter methanol wash is used to clean the inlet pipe.

The filtrate was concentrated to a volume of 50-60 L by vacuum distillation. This concentrated solution was transferred to a 170 L reactor containing sponge A-7000 (5.0 kg, 50% aqueous humidity). The solution was purged with nitrogen (3 x 50 psi). The reactor was then pressurized to 50 psi with hydrogen and stirred overnight.

The hydrogen pressure was released and the solution was purged with nitrogen. The solution is filtered into a 170 L distillation apparatus and the filter and line are rinsed with 30 L methanol. The filtrate was concentrated by vacuum distillation to a volume of 25-35 L and then made up to 30 L of isopropyl alcohol. Concentrate the solution by vacuum distillation to 18 L.

Isopropyl alcohol (20 L) and water (5 L) were added and the solution was heated to 60-65 ° C. Add glacial acetic acid (2.9 kg, 47.7 mol) and heat the solution at reflux.

Add water (8 L) to form a solution. The solution is rapidly cooled to 50 ° C and then cooled to -5 ° C ± 5 ° C for more than 5.5 hours.

The suspension is maintained at -5 ° C ± 5 ° C for about 10 hours and then filtered and washed with isopropyl alcohol (10 L). The solvent-moistened filter cake is placed in a 170 L still, followed by water (20 L) and isopropyl alcohol (40 L).

The suspension is heated at reflux to form a clear solution, which is filtered into a 170 L reactor.

The solution is rapidly cooled to 50 ° C and then cooled to -5 ° C ± 5 ° C for more than 3.5 hours. The suspension is maintained at -5 ° C ± 5 ° C for about 16 hours.

The solid was filtered off and washed with isopropyl alcohol (10 L). The solid was dried under vacuum at 45 ° C for 3 days to give 4.0 kg (57%) of pregabalin as a white solid (99.84% S).

Example 5

Hydrogenation of 3-cyano-5-methylhex-3-enoic acid (free acid)

catalytic converter -> -

MeOH

substance MH number mmol 3-Cyano-5-methylhex-3-enoic acid 153 200 mg 1,307 [(S, S) -Me-BPE] Rh (COD) ⁺ BF ₄ ' 618.48 20 mg 0.0327 (2.5 mol%) methanol 4 ml hydrogen 0.4 MPa

A. The free hexanoic acid was dissolved in methanol and a chiral catalyst was added to the solution. The mixture was shaken for 19 hours at 24 ° C under nitrogen at 50 psi. The sample was analyzed by proton NMR and the reaction was determined to be 24% complete, with cyanohexanoic acid having 95% (S) (except for errors).

One equivalent amount (0.18 mL) of triethylamine was added to the reaction mixture and shaking was continued for 5 hours (24 ° C, 0.34 MPa). The reaction mixture was filtered and the solvent was removed by evaporation.

The product was analyzed by proton NMR and showed to contain about 45% of the desired (S) -3-cyano-5-methylhexanoic acid having 95% of the S-enantiomer (except for errors).

C. The above procedure was continued by reacting 250 mg (1.634 mmol) of 3-cyano-5-methylhex-3-enoic acid with hydrogen (50 psi) in the presence of 8 mg (0.01634 mmol) of [(S, S) -Et-BPE]. 1 H (COD) ⁺ BF ₄ ^- and 0.023 ml (0.1634 mmol, 0.1 eq) of triethylamine in 5 ml of methanol at 24 ° C for 40 hours. The reaction mixture was filtered, the solvent was removed by evaporation and proton NMR showed the product to be 71% of (S) -3-cyano-5-methylhexanoic acid with 84% of the S-enantiomer (except for errors).

D. The above procedure was repeated except that no base was added to the reaction mixture. Proton NMR showed the product to be 26% (S) -3-cyano-5-methylhexanoic acid with 91% S-enantiomer (except for errors).

E. This procedure was continued by reacting (S) -3-cyano-5-methyl-3-hexanoic acid (200 mg, 1.307 mmol) with hydrogen (50 psi, 100 hours) in the presence of 10 mg (0.01307 mmol) [(S)]. (S) -Et-DuPHOS] Rh (COD) ⁺ BF ₄ '.

Proton NMR showed the product to be 82% of (S) -3-cyano-5-methylhexanoic acid with 56% of the S-enantiomer (except for errors).

F. The procedure of Example 5D was repeated except that 0.1 eq. (0.02 mL, 0.1307 mmol) of triethylamine to the reaction mixture. The reaction was stopped after 16 hours and turned out to be 86% of (S) -3-cyano-5-methylhexanoic acid with 68% of the S-enantiomer (except for errors).

G. The procedure of Example 5E was repeated except that 1 eq. Triethylamine (0.18 mL, 1.307 mmol) was added to the reaction mixture and the reaction was stopped after 16 hours. Proton NMR showed the product to be 92% converted to (S) -3-cyano-5-methylhexanoic acid having 56% S-enantiomer (except for errors).

H. In accordance with the above general procedures, 250 mg (1.634 mmol) of (S) -3-cyano-5-methylhexanoic acid was reacted with hydrogen (0.34 MPa for 16 hours, 24 ° C) in the presence of 12 mg (0.01634 mmol) [ (R, R) -DIPAMP 1 R h (COD) ⁺ BF ₄ in methanol (10 mL) to give 51% 3-cyano-5-methylhexanoic acid having 72% R-enantiomer (except for errors).

Example 6

Recrystallization of pregabalin

Solid pregabalin (117 kg, 753 mol) containing 0.6% of the (R) -enantiomer was mixed with water (550 L; 4.7 L / kg pregabalin) and isopropyl alcohol (1,100 L, 9.4 L / kg pregabalin) .

The mixture is heated to dissolve the solids (about 75 ° C ± 5 ° C), filtered hot and cooled to 0 ° C ± 5 ° C to crystallize the product. The solid was collected on a centrifuge and rinsed with isopropyl alcohol.

The wet solid is dried under vacuum at 35-45 ° C and then milled to give 91.8 kg (78.5%) of pregabalin as a white crystalline solid. The ratio of enantiomers is 99.94% of the (S) -enantiomer (pregabalin) and 0.06% of the (R) -enantiomer.

The invention and the manufacturing method and process and their use are now described in such complete, clear, concise and precise terms as to enable any person skilled in the art to carry out and use the same. It is to be understood that the foregoing describes preferred embodiments of the present invention and modifications may be made therein without departing from the spirit or scope of the present invention as set forth in the claims. In addition to the particularly emphasized and clearly emphasized nature of the solution considered to be the invention, the following claims conclude this description.

PATENT CLAIMS

Claims (12)

1. A process for the preparation of a (S) -3-cyano-5-methylhexanoic acid of formula (5) ^H 3 ^C \ L ^ X ^ ^CN CH- S < wherein X is CO ₂ H or CO ₂ -Y and Y is a cation; characterized in that the alkene of formula (4) is hydrogenated asymmetrically catalytically in the presence of a chiral catalyst. The method of claim 1, wherein X is CO ₂ -Y. The process of claim 1, wherein the chiral catalyst is a rhodium complex of (R, R) -DuPHOS ligand, wherein the ligand has the general formula (6) (6), wherein R is alkyl of 1 to 6 carbon atoms. The method of claim 3, wherein [Rh (ligand) (COD)] BF ₄ . Method according to claim 3, characterized by The method according to claim 1, characterized by or a mixture of these geometric isomers. The method according to claim 1, characterized by calic soil. Method according to claim 7, characterized by The process of claim 1, wherein the secondary amine salt is present. Method according to claim 9, characterized by Process according to claim 1, characterized in that the ester of formula (Ia) is characterized in that the chiral catalyst is that R is methyl or ethyl. wherein the alkene is an E isomer or the Z isomer wherein the cation is an alkali metal or a metal, wherein the alkali metal is potassium. in which the cation is a primary amine salt or in which the amine is tert-butylamine. further comprising first converting a carboxy (Ia) wherein R ¹ is an alkyl of 1 to 6 carbon atoms to a carboxylate salt of formula (4a) ΎΎ CN ¹ k ^ CO ₂ 'Y (4a), wherein Y is a cation. Method according to claim 11, characterized in Method according to claim 11, characterized by rogenation. wherein R ¹ is ethyl. characterized in that the carboxylate salt is isolated prior to the hydrobromide. The method of claim 11, wherein the carboxylate salt is prepared in situ before hydrogenation. Method according to claim 8, characterized in further comprising acidifying the carboxylate (S) -3-cyano-5-methylhexanoic acid salts to form (S) -3-cyano-5-methylhexanoic acid. Compound of general formula (4a)